Solutions of adrenergic compounds, in particular epinephrine and modifications thereof, find wide application for medicinal purposes. Epinephrine is one of the neural hormones responsible for the regulation of the heart, blood pressure, airway resistance, and energy metabolism. Epinephrine generates an inotropic effect, wherein it increases the heart rate, the force of contraction of the heart, narrows the blood vessels thus increasing blood pressure, reduces airway resistance to make it easier to breathe, and raises blood glucose and blood fatty acids to supply the body energy during stress. Its uses include at least combatting low blood pressure during hemorrhagic, allergic or anaphylactic shock; opening the airways during asthmatic attack; restricting the distribution of locally administered drugs such as local anaesthetics; reducing nasal congestion; and/or performance aid in emergency situations.
Catechol compounds such as epinephrine are sensitive to oxidation to o-quinones, which can react further to form highly coloured compounds. Epinephrine can thus react to form adrenochrome, a highly coloured indole derivative. The rate of this reaction increases with pH, temperature and by the presence of metal ions, such as aluminium from various rubbers and iron from amber glassware. Epinephrine solutions may also lose potency as a result of racemisation and protection from light minimises this form of instability.
The modification or degradation of the catechol amines is undesirable for a number of reasons. Modification of the catechol amine results in loss of titer of the active ingredient, formation of compounds which may have undesirable physiological effects, and the appearance of a dark colour, which makes the solution offensive and unmarketable. The initial loss of active compound due to auto-oxidation during the preparation and packaging of such a solution is substantial despite the fact that such procedures are carried out as nearly as practically possible in an inert atmosphere and such a solution must be stored under refrigeration in order to decrease the rate of deterioration of the compound and thus prolong its shelf-life.
It is standard practice, in order to stabilise adrenergic compounds such as catechol amines against auto-oxidation, to combine therewith an antioxidant. Various antioxidants which have been used to stabilise catechol amine solution in a variety of formulations such as aerosols, eye-drops, injections etc, include: metabisulfite, bisulfite, sulfite, ascorbic acid, thiglycollate, thioglycerol, cysteine, propyl gallate and formaldehyde sulfoxylate.
A commercially available epinephrine formulation is the Epipen® formulation. The composition of the Epipen® formulation, designed to deliver a minimum of 0.3 g epinephrine in a 0.3 ml injection volume, is as follows:
Epinephrine1.1mgSodium chloride6.0mgSodium metabisulfite1.7mgHydrochloric acidto pH 3.4Water for injectionto 1ml
GB 425,678 discloses a process for producing a substantially stable anesthetic solution for local anesthesia containing an acid salt of an anesthetic, epinephrine or a physiological equivalent normally requiring an acid to keep it stable and an antioxidant, which comprises adjusting the pH value of the solution by a buffer so that the solution has a pH value within a range from approximately 5.7 up to approximately neutral. Sodium bisulfite is mentioned as antioxidant.
GB 930,452 and U.S. Pat. No. 3,149,035 disclose stable pharmaceutical solutions of a catechol amine comprising an aqueous solution of the catechol amine together with oxine, boric acid, and sodium bisulfite, said solutions having a pH of 6.5-6.8.
U.S. Pat. No. 3,966,905 discloses stabilised catechol amine solutions comprising a catechol amine, a polyvinylpyrrolidone, borate and a physiologically acceptable antioxidant selected from the group consisting of ascorbic acid, erythorbic acid, acetylcysteine, and thioglycerol, at a substantially neutral or mildly basic pH.
CA 981182 discloses the stabilisation of I-epinephrine in a local anesthetic solution by using a combination of three specific antioxidants, i.e. bisulfite, ascorbic acid and thioglycerol, said solution comprising a local anesthetic selected from mepivacaine, bupivacaine and lidocaine, l-epinephrine, bisulfite, ascorbic acid and thioglycerol, and wherein said solution is of a pH of approximately 4.
US 2008/0269347 A1 discloses epinephrine formulations comprising epinephrine, EDTA, and at last one antioxidant, wherein the antioxidant is selected from the group consisting of cysteine, citric acid, thioglycerol, acetylcysteine, and a combination thereof.
DD-A1-150 694 discloses a formulation containing epinephrine hydrogen tartrate and sodium metabisulfite.
WO 94/13274 discloses formulations containing dobutamine hydrochloride and sodium metabisulfite.
WO 97/16196 discloses a formulation containing epinephrine and sodium metabisulfite.
WO98/20869 discloses a formulation containing epinephrine and sodium metabisulfite.
U.S. Pat. No. 4,734,438 discloses a formulation containing norepinephrine and sodium bisulfite.
There remains a need for a stabilised composition having an improved shelf-life stability with a substantially reduced susceptibility of light induced, thermal and oxidative degradation.